During the last few years, we have created new rodent Parkinsons disease (PD) models that mimic the progressive disease development in PD patients. With these models, we have elucidated the novel mechanisms of microglial activation that lead to inflammation-mediated neurodegeneration. For the last year, the major effort was the elucidation of signaling pathways leading to the progressive dopaminergic neuron degeneration.[unreadable] Previous work from our laboraotry demonstrrates that the interplay between the activaiton microglia and continuing neuronal death/damage is crucial in the generation of chronic inflammation and fomation of the vicious cycle. we then asked the next question "how the prolonged microglia activation was maintained". To address this issue, we studied roles of reactive microgliosis in the maintenance of the vicious cycle. For this purpose, we used MPTP as a prototype of toxin to trigger reactive microgliosis as a result of the initial insult on neurons.[unreadable] MPTP has been used as standard neurotoxin for animal PD model due to its selective toxic effect of dopaminergic neurons. This neurotoxin is also useful for us to elucidate the cellular and molecular mechanism how damaged neurons communicate with glial cells to initiate reactive gliosis, including reactive microgliosis. Direct damage to neurons can also occur with other environmental toxins or acute insults to the CNS, such as head trauma or cerebral hemmorage. It is known that stressed and injured neurons will interact with surrounding glial cells including microglia to stimulate their recruitment, proliferation and activation. We showed that within 1-2 days, MPTP caused initial DA neuron loss (20-30%) in neuron/glia cultures, which followed by a second phase of decrease of neuron number 4-5 days later (another 30-40%). We further demonstrated that the later phase of MPTP-induced neuron damage was associated with an activation of microglia, since inhibition of microglial activation prevented the second phase loss of dopaminergic neurons. A series of studies were conducted in an effort to decipher the molecular mechanism underlying the reactive microgliosis. Recent reports from our laboratory and others suggest that a spectrum of noxious endogenious compounds in extracellular milieu, generated following neuron injury, can service as stimuli to activate microglia leading to reactive microgliosis. These compounds include, but are not limited to, membrane breakdown products, abnormally processed, modified or aggregated proteins (e.g.alpha-synuclein and beta-amyloid), altered molecules (e.g. active form of matrix metalloproteinase-3), imbalanced neurotransmitters (e.g. elevated glutamate), or released or leaked cytosolic compounds (e.g. alpha-synuclein and neuromelanin). It appears that the microglial response to these endogenous toxic signals resembles their response to invading microbes. The pattern recognition receptors expressed broadly on microglia, can react to these aberrant endogenous ligands from damged neurons. In fact, we and others reported that the above-mentioned endogenous compounds exerted potent neurotoxicity in neuron/glia cultures through the activation of microglia.